Method for the preparation of pre-filled plastic syringes

ABSTRACT

A novel method for the preparation of a pre-filled plastic syringe, and preferably the preparation of a plastic syringe pre-filled with a diagnostic contrast agent, wherein said syringe comprises as components a barrel, a tip seal capable of sealing the nozzle of the barrel and a piston capable of sliding in the barrel and sealing the open end of the barrel opposite the nozzle, comprising the steps of (a) providing at least one component of said syringe which is molded under conditions which are substantially free of pyrogens and viable and non-viable particulates; and (b) filling and assembling said syringe.

FIELD OF THE INVENTION

The present invention relates to a novel method for the preparation ofpre-filled plastic syringes, and preferably to the preparation ofplastic syringes pre-filled with diagnostic contrast agents.

BACKGROUND OF THE INVENTION

Plastic syringes, pre-filled with liquid or semi-solid materialssuitable for diagnosis and/or treatment of medical conditions, findutility in the pharmaceutical arts. As can readily be appreciated, it isdesirable that such syringes are sterile and contain minimal amounts ofpyrogens and viable and non-viable particulates.

Methods for preparing pre-filled plastic syringes have previously beendisclosed. For example, U.S. Pat. No. 4,718,463 describes a method forthe preparation of pre-filled plastic syringes comprising, among othersteps, a step wherein the barrel of the syringe is washed with amultiplicity of jets of water to remove debris and pyrogens from thebarrel, followed by assembly and filling of the syringe and a terminalautoclaving step wherein the filled syringe and its contents aresterilized.

SUMMARY OF THE INVENTION

The present invention provides a method for the preparation of apre-filled plastic syringe, comprising the steps of:

(a) providing at least one component of said syringe which is moldedunder conditions which are substantially free of pyrogens and viable andnon-viable particulates; and

(b) filling and assembling said syringe. Preferably, the syringecomprises as components a barrel, a tip seal capable of sealing thenozzle of the barrel and a piston capable of sliding in the barrel andsealing the open end of the barrel opposite the nozzle, and further,said at least one component in step (a) includes one or more of thebarrel, the tip seal and/or the piston. Most preferably, said at leastone component in step (a) includes at least the barrel of the syringe.The present invention also provides a novel method for molding a syringecomponent, such as a barrel, tip seal or piston, comprising the step ofmolding said component under conditions which are substantially free ofpyrogens and viable and non-viable particulates.

The method of the present invention, wherein at least one of theaforementioned components, preferably at least the barrel, is moldedunder conditions which are substantially free of pyrogens and viable andnon-viable particulates, allows the preparation of a pre-filled plasticsyringe in a less cumbersome and more efficient manner than knownmethods by obviating the need for subsequent treatment steps such aswater washing. Thus, while the component(s) molded under conditionswhich are substantially free of pyrogens and viable and non-viableparticulates may optionally be treated subsequent to molding, such as bywater washing, such subsequent steps may be omitted or reduced inintensity or duration by use of the present method.

Preferably, the component(s) molded under conditions which aresubstantially free of pyrogens and viable and non-viable particulates inaccordance with step (a) are maintained under clean conditions untilthey are assembled in the syringe. In this regard, it is furtherpreferred that clean conditions be maintained at least until the syringeis completely assembled (for example, that the partly assembled syringebe maintained under clean conditions). Thus, in a preferred embodiment,the present invention provides a method for the preparation of apre-filled plastic syringe, wherein said syringe comprises theaforementioned barrel, tip seal and piston, comprising the steps of:

(a)

(i) providing a barrel which is molded under conditions which aresubstantially free of pyrogens and viable and non-viable particulates,and, optionally, providing a tip seal and/or a piston which is alsomolded under conditions which are substantially free of pyrogens andviable and non-viable particulates; and

(ii) maintaining said barrel and, optionally, said tip seal and/orpiston, under clean conditions for use in step (b); and

(b) filling and assembling said syringe.

In a particularly preferred embodiment, the present invention provides amethod for the preparation of a pre-filled plastic syringe, wherein saidsyringe comprises the aforementioned barrel, tip seal and piston,comprising the steps of:

(a)

(i) providing a barrel which is molded under conditions which aresubstantially free of pyrogens and viable and non-viable particulates,and, optionally, providing a tip seal and/or a piston which is alsomolded under conditions which are substantially free of pyrogens andviable and non-viable particulates; and

(ii) maintaining said barrel and, optionally, said tip seal and/orpiston, under clean conditions for use in step (b); and

(b) filling and assembling said syringe, wherein:

(i) the tip seal is attached to the nozzle end of said barrel;

(ii) the barrel and tip seal assembly is filled with a liquid orsemi-solid through the open end of the barrel, said open end beingopposite said nozzle end of the barrel; and

(iii) the piston is assembled in said open end of the barrel; and

(c) optionally, sterilizing the assembled syringe and its contents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of a pre-filled plastic syringe prepared bythe present method.

FIG. 2 is a table defining the airborne particulate cleanliness classesin accordance with Federal Standard 209(E) of Sep. 11, 1992:

FIG. 3 shows three tables indicating classes of microbial levels underdifferent conditions as set forth in Pharmacopeial Forum, Vol. 18, No.55 pp. 4048-54 (Sept.-Oct. 1992).

DETAILED DESCRIPTION OF THE INVENTION

A preferred configuration of a pre-filled plastic syringe prepared bythe present method is illustrated in FIG. 1. As can be seen from FIG. 1,the barrel 1 has a nozzle end 2, to which is attached a tip seal 3 and,at the opposite end 4, a plunger (or piston) 5. The piston may bedepressed to express the liquid or semi-solid contents 6 of the syringethrough the nozzle end.

According to the present method, at least one syringe component,preferably at least the barrel, is molded under conditions which aresubstantially free of pyrogens and viable and non-viable particulates.The term "molded under conditions which are substantially free ofpyrogens and viable and non-viable particulates", as used herein,denotes molding under conditions meeting or exceeding Class 100,000conditions with respect to particulates (Federal Standard No. 209E,"Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones,approved by the General Services Administration (Sept. 11, 1992); seeFIG. 2, Table 1, and, with respect to microbes, meeting or exceedingClass MCB-3 conditions (Pharmacopeial Forum, Volume 18, Number 5, pp.4048 to 4054, In-Process Revision, The United States PharmacopeialConvention, Inc. (Sept.-Oct. 1992); see FIG. 3, Table 2, 3 and 4, and,in addition, wherein the microbial level of gram negative microorganismsis less than 1 cfu (colony forming unit) per cubic foot of air (and,preferably, also per 30 cm² of surface). Class MCB-3 conditions, and/orthe aforementioned level of gram negative organisms, may be maintained,for example, by sampling to determine the level of microbes present, andsanitizing or employing other control methods as required (e.g., bysurface contact with alcohol, phenolic germicides such as "germwarfare®", or chlorite salts such as sodium chlorite salts (e.g.,"Exspore")). As is understood by one of ordinary skill in the art,"meeting or exceeding" denotes a level of cleanliness which is equal toor greater than the standard referred to.

With respect to particulates, the term "molded under conditions whichare substantially free of pyrogens and viable and non-viableparticulates", as used herein, preferably denotes molding underconditions meeting or exceeding Class 10,000 conditions (see FIG. 2Table 1); more preferably, conditions meeting or exceeding Class 1,000conditions (see FIG. 2 Table 1; and most preferably, under conditionsmeeting or exceeding Class 100 conditions (see FIG. 2, Table 1). Withrespect to microbes, the term "molded under conditions which aresubstantially free of pyrogens and viable and non-viable particulates",as used herein, preferably denotes molding under conditions meeting orexceeding Class MCB-2 conditions (see FIG. 3, Table 2, 3, and 4); andmore preferably, conditions meeting or exceeding Class MCB-1 conditions(see FIG. 3, Table 2, 3, and 4).

In addition to conducting the molding step under conditions which aresubstantially free of pyrogens and viable and non-viable particulates(that is, under the classified conditions described above), it ispreferred to employ an elevated temperature and/or pressure duringmolding, for example, a temperature and/or pressure where pyrogens, ifpresent, may be partly or completely decomposed during molding. Also, ifdesired, the starting plastic material may be treated, for example,washed, such as with an aqueous (e.g., water for injection) or organicwashing agent and/or sterilized, such as treated with ethylene oxide orirradiated, prior to molding.

Preferably, as indicated above, a component molded under conditionswhich are substantially free of pyrogens and viable and non-viableparticulates is maintained under clean conditions prior to assembly intothe syringe. "Clean conditions" include those defined above forconditions which are substantially free of pyrogens and viable andnon-viable particulates, but may also include any art-recognizedconditions for maintaining cleanliness such as enclosure in a sealedclean-room bag or wrapper for storage.

A syringe component molded under conditions according to step (a) of themethod of the present invention may be provided which is substantiallyfree of pyrogens and viable and non-viable particulates and which issuitable for assembly into a sterile syringe with minimal or no furthertreatment of the component prior to assembly. Thus, for example, acomponent such as the barrel molded under the conditions of step (a) ofthe present method may be assembled into the syringe without waterwashing. If desired, however, some further treatment may, optionally, beemployed subsequent to molding.

In this regard, any of the components of the syringe, including thosemolded under the conditions of step (a) of the present method, as wellas those molded under other conditions ("non-classified conditions"),may optionally be treated by one or more of the following stepssubsequent to molding:

(1) blowing the component with a gas, especially with sterile filtered(e.g., filtered through a 0.2 μm filter) and/or deionized (facilitatinga decrease in the electrostatic attraction of particles to the moldedcomponent) air to remove particulate matter;

(2) lubricating the component, such as by treatment with a siliconelubricant;

(3) washing the component with an inorganic (e.g., hydrogen peroxide orwater) and/or organic (e.g., freon) washing agent, and, optionally,rinsing the component, such as with water;

(4) sterilizing the component, such as by contact with an antimicrobialagent (for example, hydrogen peroxide (e.g., in liquid or vapor form) orethylene oxide), by use of radiation (especially, gamma radiation),and/or by autoclaving (such as by use of steam at temperatures of 122°to 124° C. and pressures of 33 to 35 psia); and/or

(5) preparing the component for storage or transport, such as by placingthe component in a sealed, clean-room bag where it is not to be employedimmediately after formation.

For those components molded under conditions which do not meet theconditions of step (a) of the present method, for example, Class 100,000conditions where microbial monitoring is not employed or other cleanroom-type conditions not meeting the conditions of step (a), it ispreferred that, at a minimum, a washing step, such as the above step (3)be employed.

Preferred Methods for Preparation of Barrel

The barrel of the syringe may be made of any suitable plastic, and ispreferably made of polyolefin, including polyolefin polymers, copolymersand blends, especially polypropylene or blends thereof withpolyethylene, or olefin polymers and copolymers including methylpentene,or the like polyolefins.

Preferably, the barrel is injection molded, such as by use of injectionmolding equipment under conditions known in the art for melting andforming plastics (e.g., injection molding polypropylene pellets intosyringe barrels by melting at 400° to 520° F. (0.75 to 3 minutes) at1000 to 1200 psi).

Preferred Methods for Preparation of Tip Seals

The tip seal of the syringe may be made of any suitable plastic, and ispreferably made of flexible rubber elastomer such as natural rubber,butyl or halobutyl rubber or blends thereof. The tip seal may be molded,preferably injection or compression molded, such as by use of injectionor compression molding equipment under conditions known in the art. Theequipment may, for example, be readily selected by one of ordinary skillin the art on the basis of the type of elastomer employed.

Preferred Methods for Preparation of Piston

The piston may be any suitable type, such as a piston operable by a rodor handle for hand injection of the contents of the syringe or a pistonoperable by a power injector for mechanical injection of the contents ofthe syringe.

The piston may be made of one, two or more pieces. The piston may, forexample, be a single piece component, or a two-piece componentconsisting of a core and a flexible cover piece attached to or fittingover or onto the core (e.g., allowing the piston to seal the barrel ofthe syringe). In the latter case, the core is preferably made of arelatively hard plastic such as a polyolefin (e.g., polypropylene) orpolycarbonate, and the flexible cover piece is preferably made of aflexible rubber elastomer, such as those materials described above withrespect to the tip seal; the two pieces may be pre-assembled to form thepiston prior to insertion into the barrel. Each of the separate piecesof the piston may be molded and optionally treated as described above.

Preferred Methods for Assembly of Syringe

In a preferred embodiment of the present method, the tip seal isassembled by attachment to the barrel, preferably automatically. Fillingmay then be conducted, such as by use of automatic filling equipment.The syringe may be filled with any suitable liquid (e.g., solution orsuspension) or semi-solid (e.g., paste, cream or ointment). Preferably,the syringe is filled with a liquid diagnostic agent suitable forinjection, for example, a contrast agent such as ProHance™ (gadoteridol)or Isovue® (iopamidol).

The liquid or semi-solid may then be sealed by insertion of the piston,optionally followed by a terminal sterilization step. When employed,sterilization is preferably achieved by steam autoclaving. Preferredtemperatures for steam autoclaving are those from about 120° to 124° C.;preferred pressures are those from about 44 to 53 psia. It isparticularly preferred to select a pressure set point so that, under theconditions of the autoclaving, the pressure inside the syringe isapproximately in equilibrium with the pressure outside the syringe inthe autoclave. An overpressure (pressure outside syringe in autoclaveexceeds that in syringe) or an underpressure (pressure in syringeexceeds that outside syringe in autoclave) may, however, also beemployed.

In addition to the tip seal, barrel and piston, the syringe prepared bythe present invention may include other components, such as any of thoseknown in the art, for example, a handle or rod for the piston, a needle,a protective cap for the needle, and the like.

The following Example further illustrates the present invention, and isnot intended to in any way limit the scope of the present claims.

EXAMPLE 1 PREPARATION OF PRE-FILLED PLASTIC SYRINGES

In the following Example, wherever Class 100 conditions are employed, itis understood that the microbial level of gram negative microorganismsis less than 1 cfu (colony forming unit) per cubic foot of air or per 30cm² of surface, and that the conditions meet or exceed Class MCB-3conditions.

Preparation of Syringe Components

(i) Barrels

Polypropylene resin pellets, prepared by extrusion of a molten (400° to520° F.) polypropylene resin mix (suitable for formation of clearplastic barrels) into pellet form, are pneumatically loaded into ahopper and fed into a sprew under Class 100,000 conditions. The pelletsare then melted at 400° to 520° F. for 0.75 to 3 minutes while under1000 to 1200 psi (also under Class 100,000 conditions). (Methylpenteneolefin resin pellets may alternatively be employed, and are preferablydried at 160° F. for 4 hours prior to being fed into the sprew.)

Under Class 100 conditions (for this and the following steps unlessindicated otherwise), the syringe barrels are formed by injectionmolding of the molten resin, and the formed barrels are pickedrobotically from the mold. The barrels are optionally blown with 0.2 μmsterile filtered, deionized air and/or lubricated with silicone. Thebarrels are then presented by the robot for visual inspection. A Class100 molded polycarbonate Luer nut may optionally be machine assembled atthis time.

Still under Class 100 conditions, the barrels are matrixed (oriented)into a Class 100 molded polypropylene carrier holder, aligning thebarrels for further processing. The barrels may optionally be placed inheat-sealed clean-room bags when stored prior to use. The barrels mayalso optionally be sterilized, such as by contact with ethylene oxide orby autoclaving. When gas sterilization is contemplated, it is preferredto place the barrels in gas permeable heat-sealed clean-room bags and tosterilize the barrels in situ.

(ii) Tip Seals

Halobutyl rubber is compression molded under Class 100,000 conditions toproduce flexible rubber tip seals. Under Class 100 conditions, the tipseals are washed with purified water, United States Pharmacopeia, XXII(1990) (hereinafter, "U.S.P., XXII") which is treated to be pyrogen freeor, preferably, water for injection, U.S.P., XXII, optionallysiliconized, and optionally placed in heat-sealed clean-room bags whenstored prior to use (gas permeable such bags may be employed when gassterilization, such as by ethylene oxide or autoclaving, in situ isdesired (see the "Assembly and Fill" section below); such bags may beother than gas permeable if it desired to employ a method ofsterilization such as irradiation).

(iii) Pistons

Two-piece pistons are prepared by assembling, preferably mechanically,under Class 100 conditions, an inner hard plastic core and a flexiblerubber cover. The pistons may optionally be placed in heat-sealedclean-room bags (preferably, gas permeable such bags when gassterilization in situ is desired) when stored prior to use and/orsterilized, such as by gamma irradiation, or, preferably, by contactwith ethylene oxide or by steam autoclaving.

Cores

The cores of the pistons are made from polypropylene (or, alternatively,polycarbonate) molded under the Class 100 conditions described above formolding the barrels. The cores may, alternatively, be molded undernon-classified conditions and washed with water for injection U.S.P.,XXII or purified water U.S.P., XXII which is treated to be pyrogen free.Optionally, the cores may be placed in heat-sealed clean-room bags(e.g., gas permeable for reasons described above) when stored prior touse.

Covers

The flexible rubber covers are molded under the conditions used toprepare the flexible rubber tip seals, and, under Class 100 conditions,are washed with water for injection U.S.P., XXII or purified waterU.S.P., XXII which is treated to be pyrogen free, and siliconized. Theflexible rubber covers may optionally be placed in heat-sealedclean-room bags (e.g., gas permeable for reasons described above) whenstored prior to use.

Assembly and Fill

The tip seals are sterilized, such as by contact with ethylene oxide orby irradiation or, preferably, by steam autoclaving, and, under Class100 conditions, are placed into the hopper of a filling machine, andassembled to the barrels. Also under Class 100 conditions, liquidcontrast agent, such as Isovue® or ProHance™, is filled into the barrelthrough the open piston end.

The two-piece pre-assembled pistons, placed into the filling machinehopper, are inserted into the barrels using a vacuum seating mechanism.The filled syringes are steam autoclaved at a temperature between 120°and 124° C. and a pressure between 44 and 53 psia. Following particulateinspection, the syringes are labeled and packaged for use.

What is claimed is:
 1. A method for the preparation of a pre-filledplastic syringe including a plurality of components, comprising thesteps of:(a) providing at least one component of said syringe which ismolded under conditions which are substantially free of pyrogens andviable and non-viable particulates, said conditions meeting acleanliness level of about Class 100; and (b) filling and assemblingsaid syringe.
 2. The method of claim 1, wherein said syringe comprisesas components a barrel, a tip seal capable of sealing the nozzle of thebarrel and a piston capable of sliding in the barrel and sealing theopen end of the barrel opposite the nozzle, and further, wherein said atleast one component in step (a) includes one or more of said barrel,said tip seal and/or said piston.
 3. The method of claim 2, wherein saidat least one component of step (a) includes said barrel.
 4. The methodof claim 3, further comprising the step of:maintaining said barrel underclean conditions for use in step (b).
 5. The method of claim 4, whereinstep (a) further includes providing a tip seal or piston or both whichare molded under conditions which are substantially free of pyrogens andviable and non-viable particulates, and maintaining all the componentsprovided in step (a) under clean conditions for use in step (b).
 6. Themethod of claim 4, wherein said step (b) comprises the steps of:(b)(i)attaching the tip seal to the nozzle end of said barrel; (ii) fillingthe barrel and tip seal assembly with a liquid or semi-solid through theopen end of the barrel, said open end being opposite said nozzle end ofthe barrel; and (iii) assembling the piston in said open end of thebarrel.
 7. The method of claim 6, wherein following step (b) theassembled syringe and its contents are sterilized.
 8. The method ofclaim 2, wherein said at least one component in step (a) is molded underconditions meeting or exceeding Class MCB-2 conditions.
 9. The method ofclaim 8, wherein said at least one component in step (a) is molded underconditions meeting or exceeding Class MCB-1 conditions.
 10. The methodof claim 2, wherein said at least one component of said syringe istreated by one or more of the following steps subsequent to molding:(1)blowing the component with a gas; (2) lubricating the component; (3)washing the component with an inorganic or organic washing agent orboth, and, optionally, rinsing the component; (4) sterilizing thecomponent; (5) preparing the component for storage or transport.
 11. Themethod of claim 10, wherein the component(s) of the syringe that are notmolded under conditions which are substantially free of pyrogens andviable and non-viable particulates in accordance with step (a) are,prior to assembly into said syringe, sterilized or washed with aninorganic or organic washing agent and optionally rinsed, or, prior toassembly into said syringe, sterilized and washed with an inorganic ororganic washing agent and optionally rinsed.
 12. The method of claim 1,wherein said at least one component in step (a) is molded underconditions meeting or exceeding Class 100 conditions.
 13. The method ofclaim 1, further comprising monitoring of microbial and non-viableparticulate levels in the molding area to maintain said conditions whichare substantially free of pyrogens and viable and non-viableparticulates.
 14. The method of claim 1, wherein said at least onecomponent of said syringe is formed from plastic, and prior to moldingthe plastic is washed with an aqueous or organic washing agent orsterilized or both washed and sterilized.
 15. A method for molding asyringe component, comprising the step of molding said component underconditions which are substantially free of pyrogens and viable andnon-viable particulates, said conditions meeting a cleanliness level ofabout Class
 100. 16. The method of claim 15, wherein said syringecomponent is a barrel, tip seal or piston.